Researchers at the University of Cincinnati have identified a novel approach to improve the effectiveness of radiation therapy for lung cancer that has spread to the brain. The study, published in Cancers, demonstrates that the drug AM-101 can enhance radiation's impact on non-small cell lung cancer (NSCLC) cells.
The Challenge of Lung Cancer Brain Metastasis
Lung cancer is the leading cause of cancer deaths in the United States. NSCLC accounts for 80-85% of cases. Up to 40% of lung cancer patients develop brain metastases, with an average survival of 8-10 months post-diagnosis. Current treatments include surgical resection, stereotactic brain radiosurgery, and whole-brain irradiation, the latter typically reserved for patients with more than 10 metastatic lesions.
"Lung cancer brain metastasis is usually incurable, and whole brain radiation treatment is palliative due to toxicity," explains Debanjan Bhattacharya, PhD, research instructor at UC's College of Medicine. "Managing side effects and overcoming radiation resistance are major challenges. New, less toxic treatments that improve radiation efficacy are crucial for improving patients' quality of life."
AM-101 and GABA(A) Receptors
The research focuses on AM-101, a synthetic analog of benzodiazepine. AM-101 is able to cross the blood-brain barrier, making it particularly useful for treating brain metastases. The team discovered that AM-101 activates GABA(A) receptors in NSCLC cells and lung cancer brain metastatic cells. This activation triggers autophagy, a process where the cell recycles and degrades unwanted components.
Specifically, the study showed that activating GABA(A) receptors increases the expression and clustering of GABARAP and Nix, boosting autophagy in lung cancer cells. This enhanced autophagy makes lung cancer cells more sensitive to radiation treatment.
Improved Survival in Animal Models
In animal models of lung cancer brain metastases, AM-101 made radiation treatment more effective and significantly improved survival. The drug also slowed the growth of primary NSCLC cells and brain metastases.
Potential for Reduced Toxicity
Combining AM-101 with radiation treatments could allow for lower radiation doses, potentially reducing side effects and toxicity. The team is now working toward opening Phase 1 clinical trials to test the combination of AM-101 and radiation in lung cancer, both within the lungs and in the brain.
